Receptor selectivity

Sex Steroid Receptors Androgen Receptor, Estrogen Receptors, Progesterone Receptor Selective Sex-steroid Receptor Modulators... 

Several steroidal and non-steroidal glucocorticoid receptor selective dissociated agonists are in development by many pharmaceutical companies and some are now in clinical development. This suggests that the development of dissociated glucocorticoids with a greater margin of safety is possible and may even lead to the development of oral compounds that do not have significant adverse effects. 

Synthetic Retinoid Receptor Selective Agonists/ Antagonists... 

Substitution of a dipeptide unit by a cychc dipeptide derivative within a peptide chain can induce certain conformational restraints that may alter the biological response via changing receptor selectivity. A facile procedure for synthesis of pyrazinone ring-containing opioid mimetics [21] has been elaborated, based on the cycHzation of readily available dipep-tidyl chloromethyl ketones [22] (Scheme 6). This method affords 2(IH)-pyrazinone derivatives containing substituents with desired functional groups at positions 3 and 6 in high yield. 

Low K, Crestani F, Keist R, et al Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290 131-134, 2000 Luddens H, Pritchett DB, Kohler M, et al Cerebellar GABAA receptor selective for a behavioural alcohol antagonist. Nature 346 648—651, 1990 LupoloverY, Safran AB, Desangles D, etal Evaluation ofvisual function in healthy subjects after administration of Ro 15-1788. Eur J Clin Pharmacol 27 505-507, 1984 Maher JF, Schreiner GE, Westervelt FB Jr Acute glutethimide intoxication 1. clinical experience (twenty-two patients) compared to acute barbiturate intoxication (sixty-three patients). Am J Med 33 70-82, 1962 Marks J The Benzodiazepines Use, Overuse, Misuse, Abuse. Baltimore, MD, University Park Press, 1978... 

Chandraratna RAS (1996) Tazarotene first of a new generation of receptor-selective retinoids. Br J Dermatol 135 18-25... 

It is obvious that strenuous efforts have been invested in the research of 5-HT receptors and, in particular, in the development of receptor-selective agonists and antagonists. All this has been done in the hope that it might be possible to control a specific switch in the brain that governs a particular aspect of 5-HT function and which would be beneficial therapeutically. A further ambition is that, by avoiding activation of other 5-HT receptors, the risk of any unwanted side-effects would be eliminated. Of course, it is equally possible that reduction in non-specific receptor interactions could actually unmask some side-effects. 

Mouse vas deferens (MVD) seems to express CB1 and at least one CB2-like cannabinoid receptor type, as is demonstrated by the presence of CB1 and CB2-like mRNA as well as by data collected from experiments with cannabinoid receptor selective agonists and antagonists (Pertwee, 1999). Furthermore, evidence indicates that a CBl-like receptor exists in vascular endothelium, which upon activation produces significant hypotension (Wagner, 1999). This receptor differs from CB1 in its pharmacological response to some well-characterized cannabimimetics. 

In 1995 the dipeptide H-Dmt-Tic-OH was reported to be a 6-opioid antagonist with unprecedented 6-receptor affinity (K = 0.022 nM) and 6 receptor selectivity (Kf/Kf = 150,000) [47]. However, in a direct comparison under identical assay conditions, this compound showed about 30 times lower 6-antagonist potency and 6 times lower 6-receptor selectivity... 

Hollt V. Opioid peptide processing and receptor selectivity, Annu Rev Pharmacol Toxicol 1986 26 59-77. 

DiMaio J, Nguyen TM-D, Lemieux C, Schiller PW. Synthesis and pharmacological characterization in vitro of cyclic enkephalin analogs effect of conformational constraints on opiate receptor selectivity. J Med Chem 1982 25 1432-1438. 

Berman JM, Goodman M, Nguyen TM-D, Schiller PW. Cyclic and acyclic partial retro-inverso enkephalins mu receptor selective enzyme resistant analogs. Biochem Biophys Res Commun 1983 115 864-870. 

Schiller PW, Weltrowska G, Nguyen TM-D, Lemieux C, Chung NN, Marsden BJ, Wilkes BC. Conformational restriction of the phenylalanine residue in a cyclic opioid peptide analogue effects on receptor selectivity and stereospecificity. J Med Chem 1991 34 3125-3132. 

Hegde VR, Dai P, Ladislaw C, Patel MG, Puar MS, Pachter JA. D4 dopamine receptor-selective compounds from the Chinese plant Phoebe chekiangensis. Bioorg Med Chem Lett 1997 7 1207-1212. 

Subtypes of /u and k receptors have also been proposed, based on pharmacological evidence [2, 14, 15]. The antagonist naloxonazine has been suggested to be a selective ligand for /ui receptors. Similarly, spiradoline and U69, 593 have been reported to be receptor-selective agonists while nor-BNI is a k1 selective antagonist. Few drugs, however, have been identified as selective for the other fi or k receptor subtypes, which has made it difficult to access their distinct functional properties. 

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